Regulation of angiogenesis and tumor progression by semaphorins

The semaphorins constitute a large family of secreted and membranebound proteins that were initially characterized as axon-guidance factors. In addition, several semaphorins, such as sema3B, sema3E, sema3F, sema4D, and a few additional less studied, were found to function as suppressors or inducers of tumor progression. These semaphorins were found to modulate tumor progression by a variety of mechanisms that include direct effects on tumor cells expressing semaphorin receptors, promotion or inhibition of tumor angiogenesis or tumor lymphangiogenesis, and recruitment or inhibition of the recruitment of various nonmalignant cell types such as bone marrow-derived cells capable of modulating tumor progression into the tumor microenvironment. In this review, we focus on the mechanisms by which semaphorins modulate tumor progression, excluding the effects of the semaphorins on the immune system, which obviously also contributes to the regulation of tumor progression.